Patient-derived organoids and mini-PDX for predicting METN375S-mutated lung cancer patient clinical therapeutic response.

Lung cancer as a molecularly and histologically high heterogonous disease, there is an urgent need to predict lung cancer patients' responses to anti-cancer treatment, and patient-derived organoids (PDOs) have been recognized as a valuable platform for preclinical drug screening. In this study, we successfully established 26 PDO lines from various subtypes of lung cancers including benign tumor, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large-cell carcinoma, and small-cell carcinoma. These PDOs were shown to retain the major genomic and histological characteristics of primary tumors and remain stable during long-term culture. With the help of targeted genomic sequencing, we found that lung cancer that harbors METN375S mutation is selectively sensitive to afatinib, and a combination of afatinib and gemcitabine induced synthetic lethality in PDO and mini-PDX models. In summary, our findings demonstrate the potential of PDO in predicting lung cancer drug response, and reveal a promising strategy for METN375S mutant lung cancer treatment.

Circ_0084653 promotes the tumor progression and immune escape in triple-negative breast cancer via the deubiquitination of MYC and upregulation of SOX5.

The role of circular RNAs (circRNAs) in cancers is gaining more and more attention, yet related reporters are limited. In triple-negative breast cancer (TNBC), circRNA circ_0084653 originated from COP9 signalosome subunit 5 (COPS5), and COPS5 has been validated to be upregulated in breast cancer before. In our research, COPS5 was also upregulated in TNBC cells, and knockdown of it repressed cell proliferation, invasion, EMT, stemness and PDL-1 protein expression but increased T-cell percentage. Further, circ_0084653 was an aberrantly upregulated circRNA in TNBC cells, and similarly, circ_0084653 silence inhibited TNBC development. Besides, circ_0084653 expression was distributed in both cytoplasm and nucleus. COPS5 overexpression partially rescued the suppressing effects of circ_0084653 depletion in TNBC. Subsequently, circ_0084653 triggered deubiquitination of MYC, the upstream transcription factor of COPS5, via recruiting ubiquitin specific peptidase 36 (USP36). Moreover, circ_0084653 served as the sponge of miR-1323 to release the expression the target gene SRY-box transcription factor 5 (SOX5). SOX5 upregulation completely remedied the inhibiting influence of circ_0084653 downregulation in TNBC. Meanwhile, transcription factor SOX5 activated transcriptionally circ_0084653. To sum up, SOX5-induced circ_0084653 promotes TNBC via the deubiquitination of USP36, which may provide some fresh ideas for TNBC-related molecular mechanisms.

Exploring the mechanisms and relationship between body mass index and asthma: findings from Mendelian randomization.

BACKGROUND: The mechanism linking BMI and asthma remains unclear. METHOD: Mendelian Randomization (MR) analysis was conducted using summary-level GWAS data from the FinnGen Biobank and the Open GWAS project. The analysis considering potential variables as mediators, including blood cell counts, blood pressure, and blood biomarkers. Three commonly used MR methods-the inverse-variance-weighted (IVW) method, weighted median (WM) method, and MR-Egger method-were employed to infer causal links. A two-step approach was used in mediation analysis to evaluate the causal links among BMI, candidate mediators, and asthma. RESULT: Elevated BMI demonstrated a substantial correlation with increased asthma risk. Thirteen biomarkers mediated the relationship between BMI and asthma, mainly including leukocyte count (5.070%), apolipoprotein A levels (7.395%), cystatin C levels (5.345%), urate levels (9.057%), diastolic blood pressure (7.365%), and albumin levels (10.888%). These factors collectively explained over 50% of the increased asthma risk associated with BMI elevation. Additionally, eosinophil count and C-reactive protein were also identified as important mediators using the WM method. CONCLUSION: This study highlights the complex relationship between obesity, blood biomarkers, and asthma risk. Additional studies are required to validate these results and investigate causal relationships in various populations.

Dried fruit, acetate, and asthma: a mediation Mendelian randomization analysis.

BACKGROUND: Asthma is a common chronic condition with increasing prevalence. Diet, including dried fruit consumption, has been linked to asthma risk, but the mechanisms remain unclear. This study investigates how dried fruit consumption affects asthma risk, focusing on acetate as a potential mediator. METHODS: We used Mendelian Randomization (MR) to analyze the relationships between dried fruit intake, acetate levels, and asthma. We applied three MR methods-Inverse-Variance Weighted (IVW), Weighted Median (WM), and MR-Egger-to determine causal effects. RESULTS: Dried fruit intake was inversely associated with asthma risk (IVW: ß = -0.506, p = 0.0135) and positively associated with acetate levels (IVW: ß = 0.269, p < 0.0001). Higher acetate levels were also linked to lower asthma risk (IVW: ß=-0.361, p < 0.0001). Mediation analysis showed that acetate mediates approximately 19.22% of the effect of dried fruit on asthma risk. CONCLUSION: Dried fruit consumption reduces asthma risk, partly through increasing acetate levels. This acetate-mediated pathway accounts for about 20% of the effect, suggesting potential for dietary strategies in asthma prevention and management. Further research could enhance the understanding and applicability of these findings.

Structural characterization and mechanisms of macrophage immunomodulatory activity of a novel polysaccharide with a galactose backbone from the processed Polygonati Rhizoma.

A purified polysaccharide with a galactose backbone (SPR-1, Mw 3,622 Da) was isolated from processed Polygonati Rhizoma with black beans (PRWB) and characterized its chemical properties. The backbone of SPR-1 consisted of [(4)-ß-D-Galp-(1]9 â†’ 4,6)-ß-D-Galp-(1 â†’ 4)-α-D-GalpA-(1 â†’ 4)-α-D-GalpA-(1 â†’ 4)-α-D-Glcp-(1 â†’ 4,6)-α-D-Glcp-(1 â†’ 4)-α/ß-D-Glcp, with a branch chain of R1: ß-D-Galp-(1 â†’ 3)-ß-D-Galp-(1→ connected to the →4,6)-ß-D-Galp-(1→ via O-6, and a branch chain of R2: α-D-Glcp-(1 â†’ 6)-α-D-Glcp-(1→ connected to the →4,6)-α-D-Glcp-(1→ via O-6. Immunomodulatory assays showed that the SPR-1 significantly activated macrophages, and increased secretion of NO and cytokines (i.e., IL-1ß and TNF-α), as well as promoted the phagocytic activities of cells. Furthermore, isothermal titration calorimetry (ITC) analysis and molecular docking results indicated high-affinity binding between SPR-1 and MD2 with the equilibrium dissociation constant (K D) of 18.8 µM. It was suggested that SPR-1 activated the immune response through Toll-like receptor 4 (TLR4) signaling and downstream responses. Our research demonstrated that the SPR-1 has a promising candidate from PRWB for the TLR4 agonist to induce immune response, and also provided an easily accessible way that can be used for PR deep processing.

Cholinized-Polymer Functionalized Lipid-Based Drug Carriers Facilitate Liver Fibrosis Therapy via Ultrafast Liver-Targeting Delivery.

Here, we report novel cholinized-polymer functionalized lipid-based nanoparticles (CP-LNPs) for rapid and highly effective delivery of drugs to the liver, achieving targeting within 10 min and nearly 100% efficiency. In this study, CP-LNPs loaded with a promising antifibrotic agent curcumin (CP-LNPs/Cur) significantly improved the stability of curcumin under physiological conditions and its distribution in the liver. In vitro experiments demonstrated that CP-LNPs/Cur effectively suppressed the proliferation and migration of activated hepatic stellate cells (aHSCs), as evidenced by the decreased expression of α-SMA. Moreover, CP-LNPs/Cur attenuated oxidative stress levels in hepatocytes while improving mitochondrial physiological activity. In vivo antifibrosis studies have shown that CP-LNPs/Cur only require a low dose to significantly alleviate liver injury and collagen deposition, thereby preventing the progression of liver fibrosis. These findings indicated that CP-LNPs exhibit great potential in liver fibrosis therapy benefiting from the novel targeting strategy.

Multi-modal deep learning enables efficient and accurate annotation of enzymatic active sites.

Annotating active sites in enzymes is crucial for advancing multiple fields including drug discovery, disease research, enzyme engineering, and synthetic biology. Despite the development of numerous automated annotation algorithms, a significant trade-off between speed and accuracy limits their large-scale practical applications. We introduce EasIFA, an enzyme active site annotation algorithm that fuses latent enzyme representations from the Protein Language Model and 3D structural encoder, and then aligns protein-level information with the knowledge of enzymatic reactions using a multi-modal cross-attention framework. EasIFA outperforms BLASTp with a 10-fold speed increase and improved recall, precision, f1 score, and MCC by 7.57%, 13.08%, 9.68%, and 0.1012, respectively. It also surpasses empirical-rule-based algorithm and other state-of-the-art deep learning annotation method based on PSSM features, achieving a speed increase ranging from 650 to 1400 times while enhancing annotation quality. This makes EasIFA a suitable replacement for conventional tools in both industrial and academic settings. EasIFA can also effectively transfer knowledge gained from coarsely annotated enzyme databases to smaller, high-precision datasets, highlighting its ability to model sparse and high-quality databases. Additionally, EasIFA shows potential as a catalytic site monitoring tool for designing enzymes with desired functions beyond their natural distribution.

Machine learning-based predictive model for the development of thrombolysis resistance in patients with acute ischemic stroke.

BACKGROUND: The objective of this study was to establish a predictive model utilizing machine learning techniques to anticipate the likelihood of thrombolysis resistance (TR) in acute ischaemic stroke (AIS) patients undergoing recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis, given that nearly half of such patients exhibit poor clinical outcomes. METHODS: Retrospective clinical data were collected from AIS patients who underwent intravenous thrombolysis with rt-PA at the First Affiliated Hospital of Bengbu Medical University. Thrombolysis resistance was defined as ([National Institutes of Health Stroke Scale (NIHSS) at admission - 24-hour NIHSS] × 100％/ NIHSS at admission) ≤ 30%. In this study, we developed five machine learning models: logistic regression (LR), extreme gradient boosting (XGBoost), support vector machine (SVM), the least absolute shrinkage and selection operator (LASSO), and random forest (RF). We assessed the model's performance by using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA), and presented the results through a nomogram. RESULTS: This study included a total of 218 patients with AIS who were treated with intravenous thrombolysis, 88 patients experienced TR. Among the five machine learning models, the LASSO model performed the best. The area under the curve (AUC) on the testing group was 0.765 (sensitivity: 0.767, specificity: 0.694, accuracy: 0.727). The apparent curve in the calibration curve was similar to the ideal curve, and DCA showed a positive net benefit. Key features associated with TR included NIHSS at admission, blood glucose, white blood cell count, neutrophil count, and blood urea nitrogen. CONCLUSION: Machine learning methods with multiple clinical variables can help in early screening of patients at high risk of thrombolysis resistance, particularly in contexts where healthcare resources are limited.

Cuttlefish Bone-Derived Calcium Phosphate Bioceramics Have Enhanced Osteogenic Properties.

Cuttlefish bones are byproducts of cuttlefish processing and are readily available in the marine food industry. In this study, calcium phosphate bioceramics were prepared from cuttlefish bones using a two-stage hydrothermal calcination process. The results indicated that all bioceramics derived from cuttlefish bones had a higher degradation capacity, better bone-like apatite formation ability, and higher degree of osteogenic differentiation than commercially available hydroxyapatite. Notably, ß-tricalcium phosphate, which had the highest degree of Ca2+ and Sr2+ dissolution among the bioceramics extracted, can significantly upregulate osteogenic markers (alkaline phosphatase, osteocalcin) and stimulate bone matrix mineralization. Thus, it is a promising bioceramic material for applications in bone regeneration.

Secoisolariciresinol diglucoside attenuates neuroinflammation and cognitive impairment in female Alzheimer's disease mice via modulating gut microbiota metabolism and GPER/CREB/BDNF pathway.

BACKGROUND: Gender is a significant risk factor for late-onset Alzheimer's disease (AD), often attributed to the decline of estrogen. The plant estrogen secoisolariciresinol diglucoside (SDG) has demonstrated anti-inflammatory and neuroprotective effects. However, the protective effects and mechanisms of SDG in female AD remain unclear. METHODS: Ten-month-old female APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with SDG to assess its potential ameliorative effects on cognitive impairments in a female AD model through a series of behavioral and biochemical experiments. Serum levels of gut microbial metabolites enterodiol (END) and enterolactone (ENL) were quantified using HPLC-MS. Correlation analysis and broad-spectrum antibiotic cocktail (ABx) treatment were employed to demonstrate the involvement of END and ENL in SDG's cognitive improvement effects in female APP/PS1 mice. Additionally, an acute neuroinflammation model was constructed in three-month-old C57BL/6J mice treated with lipopolysaccharide (LPS) and subjected to i.c.v. injection of G15, an inhibitor of G protein-coupled estrogen receptor (GPER), to investigate the mediating role of the estrogen receptor GPER in the cognitive benefits conferred by SDG. RESULTS: SDG administration resulted in significant improvements in spatial, recognition, and working memory in female APP/PS1 mice. Neuroprotective effects were observed, including enhanced expression of CREB/BDNF and PSD-95, reduced ß-amyloid (Aß) deposition, and decreased levels of TNF-α, IL-6, and IL-10. SDG also altered gut microbiota composition, increasing serum levels of END and ENL. Correlation analysis indicated significant associations between END, ENL, cognitive performance, hippocampal Aß-related protein mRNA expression, and cortical neuroinflammatory cytokine levels. The removal of gut microbiota inhibited END and ENL production and eliminated the neuroprotective effects of SDG. Furthermore, GPER was found to mediate the inhibitory effects of SDG on neuroinflammatory responses. CONCLUSION: These findings suggest that SDG promotes the production of gut microbial metabolites END and ENL, which inhibit cerebral ß-amyloid deposition, activate GPER to enhance CREB/BDNF signaling pathways, and suppress neuroinflammatory responses. Consequently, SDG exerts neuroprotective effects and ameliorates cognitive impairments associated with AD in female mice.

Skeleton-guided multi-scale dual-coordinate attention aggregation network for retinal blood vessel segmentation.

Deep learning plays a pivotal role in retinal blood vessel segmentation for medical diagnosis. Despite their significant efficacy, these techniques face two major challenges. Firstly, they often neglect the severe class imbalance in fundus images, where thin vessels in the foreground are proportionally minimal. Secondly, they are susceptible to poor image quality and blurred vessel edges, resulting in discontinuities or breaks in vascular structures. In response, this paper proposes the Skeleton-guided Multi-scale Dual-coordinate Attention Aggregation (SMDAA) network for retinal vessel segmentation. SMDAA comprises three innovative modules: Dual-coordinate Attention (DCA), Unbalanced Pixel Amplifier (UPA), and Vessel Skeleton Guidance (VSG). DCA, integrating Multi-scale Coordinate Feature Aggregation (MCFA) and Scale Coordinate Attention Decoding (SCAD), meticulously analyzes vessel structures across various scales, adept at capturing intricate details, thereby significantly enhancing segmentation accuracy. To address class imbalance, we introduce UPA, dynamically allocating more attention to misclassified pixels, ensuring precise extraction of thin and small blood vessels. Moreover, to preserve vessel structure continuity, we integrate vessel anatomy and develop the VSG module to connect fragmented vessel segments. Additionally, a Feature-level Contrast (FCL) loss is introduced to capture subtle nuances within the same category, enhancing the fidelity of retinal blood vessel segmentation. Extensive experiments on three public datasets (DRIVE, STARE, and CHASE_DB1) demonstrate superior performance in comparison to current methods. The code is available at https://github.com/wangwxr/SMDAA_NET.

Evaluation of genotoxicity and teratogenicity of phillyrin.

Phillyrin is extracted from Forsythia suspensa (Thunb.) Vahl, is significantly higher in (unripe Forsythiae Fructus) Qing qiao than in (ripe Forsythiae Fructus) Lao qiao fruits of the plant. However, the toxicity of phillyrin has not been adequately investigated. The study investigates the genetic and teratogenic effects of phillyrin to determine its safety profile. Assessing the genotoxicity and teratogenicity of phillyrin involved various tests, such as the bacterial reverse mutation assay, mammalian erythrocyte micronucleus assay, spermatocyte chromosome aberration assay, and teratogenicity assay. The results demonstrated that phillyrin exhibited no discernible impact on the following: number of colonies that spontaneously revert for Salmonella typhimurium TA 97, TA98, TA100, TA102, and TA1535, frequency of bone marrow polychromatic erythrocytes, and the rate of chromosomal aberrations. In the teratogenicity test, the pregnant rats exhibited no signs of toxicity or abnormal changes, and the growth, embryonic development, and visual anatomy of each pup were normal. In comparison with the negative control group, there were no significant differences in fetal body weight, mortality, deformity rate, malformed nest rate, gravid uterus weight, average number of fetuses per litter, fetal body length, or visceral and skeletal development in each dose group. In conclusion, these findings provide evidence that phillyrin does not exhibit genotoxic or teratogenic effects, supporting its potential safety for pharmacological applications.

Mechanism of multifunctional adaptor protein SHARPIN regulating myocardial fibrosis and how SNP mutation affect the prognosis of myocardial infarction.

Myocardial fibrosis (MF) is characterized by the excessive deposition of extracellular matrix within the heart, often following a cardiovascular insult. SHARPIN, a protein implicated in fibrosis, has emerged as a potential therapeutic target. This study aimed to elucidate the molecular mechanisms of SHARPIN in MF and to investigate the influence of its single nucleotide polymorphism (SNP), rs117299156, on myocardial infarction (MI) patients. A mouse model of Angiotensin II (AngII)-induced MF was established in SHARPIN heterozygous (SHARPIN+/-) and wild-type mice. Adult mouse cardiac fibroblasts (CFs) were isolated and subjected to adenovirus-encapsulated SHARPIN short hairpin RNA (shRNA) infection. Transcriptomic analysis was performed on CFs from SHARPIN+/- and wild-type (WT) mice, complemented by single-cell sequencing data from human cardiac tissues. Additionally, the association between the rs117299156 mutation and cardiovascular events in MI patients was assessed. Our findings indicate that SHARPIN is predominantly expressed in CFs and is upregulated in fibrotic myocardium. Partial knockdown of SHARPIN in murine hearts mitigated AngII-induced cardiac dysfunction and MF. Furthermore, reduced SHARPIN expression in CFs attenuated TGF-ß1-induced collagen synthesis, cell proliferation, and myofibroblast transformation. Notably, MI patients carrying the rs117299156_C allele exhibited a reduced incidence of stroke events compared to those without the mutation.

Microfluidic Engineering of Addressable Multicompartmental Microspheres for Multicellular Systems.

With the advantages of high-throughput manufacturing and customizability, on-microsphere construction of in vitro multicellular analytical systems has garnered significant attention. However, achieving a precise, biocompatible cell arrangement and spatial signal analysis in hydrogel microspheres remains challenging. In this work, a microfluidic method is reported for the biocompatible generation of addressable supersegmented multicompartmental microspheres. Additionally, these microspheres are developed as novel label-free multicellular systems. In the microfluidic approach, controllable microfluidics is used to finely tune the internal microstructure of the microspheres, and the gas ejector ensures the biocompatibility of the preparation process. As a proof of concept, six- and twenty-compartment microspheres were obtained without the addition of any biohazardous reagents. For microsphere decoding, the visualization of two basic compartments can provide clues for identifying label-free cells due to the structural regularity of the microspheres. Finally, by encapsulating cells of different types, these microspheres as multicellular systems were successfully used for cell coculture and drug testing. These biocompatible, scalable, and analyzable microspheres will open up new prospects for biomedical analysis.

Exploration of ETV6::ABL1-positive AML with concurrent NPM1 and FLT3-ITD mutations.

ETV6::ABL1 is a rare fusion gene that found in MPN, ALL, and AML. It has a complex and diverse formation mechanism due to the reciprocal orientations of the ETV6 and ABL1 genes relative to the centromeres. NPM1 is frequently mutated in adult AML, often accompanied by FLT3-ITD, which suggests molecular synergisms in AML pathogenesis. Previous reports on ETV6::ABL1 mostly focus on FLT3-ITD. In this study, we present a case of AML with ETV6::ABL1, along with NPM1 and FLT3-ITD. The patient showed a rapid increase in primitive cells at the initial stage, along with the presence of immature granulocytes and erythrocytes. Through cytogenetic analysis, fluorescence in situ hybridization (FISH), and RNA-seq, we elucidated the mechanism behind the formation of the ETV6::ABL1 fusion gene. Despite conventional chemotherapy failure and rapid tumor proliferation, we attempted to add FLT3 inhibitor sorafenib to the treatment, along with chemotherapy bridging to haploidentical transplantation. After haplo-HSCT, a combination of sorafenib and dasatinib was administered as maintenance therapy. The patient achieved complete remission (CR) and maintained it for 11 months. The intricate genetic landscape observed in this case presents diagnostic dilemmas and therapeutic challenges, emphasizing the importance of a comprehensive understanding of its implications for disease classification, risk stratification, and treatment selection.

Shufeng Jiedu capsule alleviates influenza A (H1N1) virus induced acute lung injury by regulating the lung inflammatory microenvironment.

Background: Death caused by respiratory tract infection is one of the leading causes of death in the world today. Shufeng Jiedu Capsule (SFJDC) is a traditional Chinese medicine that has been widely used clinically for coronavirus disease 2019 (COVID-19), H1N1 influenza virus pneumonia and other diseases. Its pharmacological effect is to inhibit inflammation and improve the body's ability to clear viruses. However, the mechanism of SFJDC in the treatment of viral pneumonia, especially its effect on the inflammatory-immune microenvironment of lung tissue remains unclear. Methods: Mice with H1N1 influenza virus pneumonia were used as a model to verify the efficacy of SFJDC through death protection, lung index, viral load, and HE staining of lung tissue. The levels of inflammatory cytokines and chemokines in lung tissue were investigated by multi-analyte immunoassay. The number and proportion of cells in peripheral blood were detected by blood routine. The percentage of infiltrating immune cells in lung tissue was detected by flow cytometry and immunofluorescence. Results: SFJDC (2.2 g/kg·d-1 and 1.1 g/kg·d-1) increased survival rate (P＜0.01, P＜0.05), prolonged the survival period of mice, and alleviated the histopathological damage in lung (P＜0.01). SFJDC (2.2 g/kg·d-1, 1.1 g/kg·d-1 and 0.055 g/kg·d-1) increased body weight(P＜0.01, P＜0.05), improved activity status, reduced the lung index (P＜0.01, P＜0.05) and viral load (P＜0.01). SFJDC (2.2 g/kg·d-1 and 1.1 g/kg·d-1) reduced interleukin-1ß (IL-1ß), interleukin-18(IL-18), tumour necrosis factor α (TNF-α), monocyte chemoattractant protein (MCP), chemokine (C-X-C motif) ligand 1 (CXCL1) (P＜0.01, P＜0.05), and SFJDC (2.2 g/kg·d-1) increased IL-10 levels (P＜0.05) to regulate inflammation. SFJDC (2.2 g/kg·d-1) increased the percentages of CD4+ T cells (P＜0.01), CD8+ T cells (P＜0.05), and B cells(P＜0.05), and decreased F4/80+ macrophages (P＜0.05). Conclusion: Our findings indicated that SFJDC could inhibit inflammation and lung injury while maintaining the function of the adaptive immune response mediated by T and B cells, and promote the clearance of the virus, thereby treating influenza A (H1N1) virus-induced pneumonia.

Fluoxetine Rescues Excessive Myelin Formation and Psychological Behaviors in a Murine PTSD Model.

Posttraumatic stress disorder (PTSD) is a complex mental disorder notable for traumatic experience memory. Although current first-line treatments are linked with clinically important symptom reduction, a large proportion of patients retained to experience considerable residual symptoms, indicating pathogenic mechanism should be illustrated further. Recent studies reported that newly formed myelin could shape neural circuit function and be implicated in fear memory preservation. However, its role in PTSD remains to be elucidated. In this study, we adopted a restraint stress-induced PTSD mouse model and found that PTSD-related neuropsychiatric symptoms were accompanied by increased myelination in the posterior parietal cortex and hippocampus. Fluoxetine, but not risperidone or sertraline, has a more profound rescue effect on neuropsychological behaviors and myelin abnormalities. Further mechanistic experiments revealed that fluoxetine could directly interfere with oligodendroglial differentiation by upregulating Wnt signaling. Our data demonstrated the correlation between PTSD and abnormal myelination, suggesting that the oligodendroglial lineage could be a target for PTSD treatment.

Real-Time pH Sensor in Bacterial Microenvironments Using Liquid Crystal Core-Shell Microspheres.

It is well-known that the bacterial microenvironment imposes restrictions on the growth and behavior of bacteria. The localized monitoring of microenvironmental factors is appreciated when consulting bacterial adaptation and behavior in the presence of chemical or mechanical stimuli. Herein, we developed a novel liquid crystal (LC) biosensor in a microsphere configuration for real-time 3D monitoring of the bacteria microenvironment, which was implemented by a microfluidic chip. As a proof of concept, a LC gel (LC-Gel) microsphere biosensor was prepared and employed in the localized pH changes of bacteria by observing the configuration change of LC under polarized optical microscopy. Briefly, the microsphere biosensor was constructed in core-shell configuration, wherein the core contained LCE7 (a nematic LC) doped with 4-pentylbiphenyl-4'-carboxylic acid (PBA), and the shell encapsulated the bacteria. The protonation of carboxyl functional groups of the PBA induced a change in charge density on the surface of LCE7 and the orientation of E7 molecules, resulting in the transitions of the LC nucleus from axial to bipolar. The developed LC-Gel microspheres pH sensor exhibited its dominant performance on localized pH real-time sensing with a resolution of 0.1. An intriguing observation from the prepared pH biosensor was that the diverse bacteria impelled distinct acidifying or alkalizing effects. Overall, the facile LC-Gel microsphere biosensor not only provides a versatile tool for label-free, localized pH monitoring but also opens avenues for investigating the effects of chemical and mechanical stimuli on cellular metabolism within bacterial microenvironments.

Identifying key inflammatory genes in psoriasis via weighted gene co-expression network analysis: Potential targets for therapy.

Psoriasis is a globally prevalent chronic inflammatory skin disease. This study aimed to scrutinize the hub genes related to inflammation and potential molecular mechanisms in psoriasis. Utilizing mRNA expression profiles from public datasets GSE13355, GSE78097, and GSE14905, we set up a comprehensive analysis. Initially, we selected differentially expressed genes (DEGs) from psoriasis and control samples in GSE13355, followed by calculating inflammatory indices using genomic set variation analysis (GSVA). Weighted gene co-expression network analysis (WGCNA) was then applied to link significant modules with the inflammatory index. This process helped us identify differentially expressed inflammation-related genes (DE-IRGs). A protein-protein interaction (PPI) network was established, with the molecular complex detection (MCODE) plug-in pinpointing six chemokine genes (CCR7, CCL2, CCL19, CXCL8, CXCL1, and CXCL2) as central hub genes. These genes demonstrated pronounced immunohistochemical staining in psoriatic tissues compared to normal skin. Notably, the CCR7 gene exhibited the highest potential for m6A modification sites. Furthermore, we constructed transcription factor-microRNA-mRNA networks, identifying 139 microRNAs and 52 transcription factors associated with the hub genes. For the LASSO logistic regression model, the area under the curve (AUC) in the training set was 1, and in the two validation cohorts GSE78097 and GSE14905 were 1 and 0.872, respectively. In conclusion, our study highlights six chemokine genes (CCR7, CCL2, CCL19, CXCL8, CXCL1, and CXCL2) as potential biomarkers in psoriasis, providing insights into the immune and inflammatory responses as pivotal instances in disease pathogenesis. These findings pave the way for exploring new therapeutic targets, particularly focusing on chemokine-associated pathways in psoriasis treatment.

Sub-pixel target fine spatial feature extraction method based on aperture coding and micro-scanning imaging mechanism.

The small imaging size of targets over long distances results in the loss of geometry and spatial features. Current methods are subject to sampling limitations and cannot accurately capture the spatial features of sub-pixel targets. This paper proposes a method to accurately locate and extract the fine spatial features of sub-pixel targets through aperture coding and micro-scanning imaging. First, the formation mechanism of imaging features for sub-pixel targets is analyzed. Second, the optical aperture is anisotropically coded in different directions to modulate the spreading spots of the target. The primary spreading direction and the center of the anisotropic spreading spots are extracted. The contour and the location of the target are determined from the spreading length and the intersections of the primary spreading directions. Then, the target is sampled by different detector units through various micro-scanning offsets. The pixel units containing different sub-pixel components of the target after offset are determined based on the location results. The fine spatial distribution of the sub-pixel target is reconstructed based on the intensity variations in the pixel units containing the target. Finally, the accuracy of the sub-pixel target fine spatial feature extraction method is validated. The results show a sub-pixel localization error of less than 0.02 and an effective improvement of the sub-pixel target spatial resolution. This paper provides significant potential for improving the ability to capture spatial features of targets over long distances.